Fenretinide [HPR; all-trans-N-(4-hydroxyphenyl)retinamide; CAS Registry number 65646-68-6] is a synthetic retinoic acid derivative having the structure:
Fenretinide is minimally soluble in aqueous solution. U.S. Pat. No. 4,665,098 by Gibbs describes an oral pharmaceutical composition of fenretinide as useful for the treatment of breast and bladder cancer. However, the bioavailability of this oral fenretinide composition is limited and greater anticancer effects might be obtained if fenretinide could be delivered intravenously to achieve higher drug plasma levels. Hence, there currently remains a need for new pharmacological compositions of fenretinide, especially for oral administration which provide for both satisfactory solubility, and plasma and tissue bioavailability, especially in patient populations generally less tolerant of capsule, tablet, or other non-chewable or non-imbibible drug delivery vectors.
Intravenous formulations of 4-HPR have recently been developed that obtain significantly higher 4-HPR plasma (30-120 μM) and tissue levels in rodent and canine animal models than the current oral capsule formulation while retaining minimal systemic toxicity (results not shown). However, this formulation is intended for use in the inpatient setting in conjunction with intravenous safingol (used as a ceramide metabolism modulator). Thus, there remains a need for an improved oral formulation of 4-HPR for outpatient use, such as in maintenance therapy during states of minimal residual disease, or in the palliative care setting, that is easier to administer and that has improved bioavailability. Such a formulation would be particularly advantageous for small children and elderly adults in which compliance with the schedules of the current oral capsular 4-HPR is problematical. Further, an improved oral formulation would facilitate the combination of 4-HPR with ceramide modulating agents in the outpatient setting.
Formulations of fenretinide suitable for high dose parenteral delivery are described in PCT Application WO 02/05869 to Gupta et al.
Formulations of fenretinide suitable for oral delivery are described in U.S. Pat. No. 5,972,911 and U.S. Pat. No. 4,874,795.